Article : Resistance to Anti–PD-1 Therapy in Melanoma Patients

Jeffrey A. Sosman, MD reviewing Zaretsky JM et al. N Engl J Med 2016 Jul 13.

Mutations preventing interferon-receptor signaling and antigen presentation are linked to acquired resistance.

A prior study showed that about a quarter of melanoma patients who responded to PD-1–blockade therapy with pembrolizumab had disease progression at a median follow-up of 21 months (NEJM JW Oncol Hematol Jul 2016 and JAMA 2016; 315:1600). To determine genetic mechanisms of acquired resistance to PD-1–blockade therapy, investigators analyzed biopsy samples from metastatic melanoma patients who experienced progression after an initial response.

Of 78 patients, 42 had objective clinical responses, and 15 of the responders progressed. Of the responders who progressed, 4 qualified for the study, since they had responses lasting more than 6 months (progression-free survival, 13–29 months), and they provided sufficient tissue before treatment and at progression for testing, which included whole-exome sequencing.

Mechanisms of resistance were identified in three of the four patients. One demonstrated the loss of β2-microglobulin expression due to mutations in both alleles preventing expression of major histocompatibility complex class I molecules on the melanoma cells and preventing the presentation of tumor antigens to the host CD8 T cells. The other two patients had acquired mutations in the JAK1 γ-interferon (IFN) signaling molecule (patient 1) and JAK2 γ-IFN signaling molecule (patient 2) that led to loss of function and prevented signaling down the JAK-STAT pathway critical to IFN signaling. Ultimately, the induction and expression of PD-L1 on the tumor-cell surface is dependent on T-cell release of γ-IFN and its binding to the γ-IFN receptor on the tumor cell.


Zaretsky JM et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016 Jul 13; [e-pub].